A Matched Molecular Pair (MMP) is defined as a pair of molecules that differ only "by a particular, well defined, structural transformation".1 The valuable information of an MMP along with the subsequent effect on pharmaceutical properties can be used to improve a lead compound regarding solubility, plasma protein binding and oral exposure.1-3 Considering the chemical environment of the structural transformation, MMPs might also be used to improve the affinity of a lead compound to a specific target. The recently described VAMMPIRE database4 was designed to link MMP transformations with the relevant receptor environment and the corresponding effect on ligand affinity. Based on VAMMPIRE database and using a atom-pair descriptor to represent the substitution environment, we developed the prediction tool LORD (Lead Optimization by Rational Design). LORD operates on the principle that molecular transformations cause similar effects in similar substitution environments and is therefore able to extrapolate the knowledge of a given substitution effect to any similar system. LORD was implemented as an easy-to-use web server that guides the user step-by-step through the optimization process of a defined lead compound.
Weber, J.; Achenbach, J.; Moser, D.; Proschak, E. VAMMPIRE-LORD: A Web Server for Straightforward Lead Optimization Using Matched Molecular Pairs J. Chem. Inf. Model., 2015, 55, 207-213. http://pubs.acs.org/doi/abs/10.1021/ci5005256
Structure-based optimization to improve the affinity of a lead compound is an established approach in the majority of drug discovery campaigns. Knowledge based databases holding molecular replacements and the consequential influence on binding affinity, like the recently published SwissBioisostere database,5 can be supportive in the optimization process. Matched molecular pairs (MMPs) which are, according to Leach et al., described "to differ only by a particular, well-defined, structural transformation",1,3 typically define the starting point for the development of those substitution databases.
In this work we introduce a strategy to relate the substitution effect, which is the change in binding affinity within a MMP, to the atom environment within the co-crystallized protein-ligand complex. The PDBbind,6,7 a collection of biomolecular complexes, with available binding affinity data, forms the basis for our calculations and is extended by the huge amount of binding affinity data deposited in the ChEMBLdb.8 By building MMPs between PDBbind and ChEMBLdb ligands (which are known to bind the same target) we were able to extrapolate the two-dimensional ChEMBLdb ligands to the assumed, three-dimensional binding mode and introduce the received binding information into our database. The resulting database VAMMPIRE (Virtually Aligned Matched Molecular Pairs Including Receptor Environment) and the supplementary web interface provide valuable information for structure-based lead optimization, but but may also be used for studies engaged in fundamental understanding of protein-ligand interactions.
Weber, J.; Achenbach, J.; Moser, D.; Proschak, E. VAMMPIRE: A Matched Molecular Pairs Database for Structure-Based Drug Design and Optimization J. Med. Chem., 2013, 56, 5205-5207. http://pubs.acs.org/doi/abs/10.1021/jm400223y